Cross Coupling Chemistry as a Tool for the Synthesis of Diverse Heterocyclic Systems and Natural Products

Cross-Coupling Chemistry as a Tool for the

Synthesis of Diverse Heterocyclic Systems and

Natural Products

A Thesis Submitted for the Degree of Doctor of

Philosophy of the Australian National University

by

Michael Elvis Dlugosch

Research School of Chemistry

Canberra, Australia

Acknowledgements

First I would like to thank my supervisor Professor Martin Banwell for having given me the

opportunity and the privilege to undertake my PhD studies in his research group. Like a captain, he

would guide me through the rough seas of my research and make sure that I would never lose track

of where I was going. He would encourage me and he would inspire me to never give up and always

keep going, even and especially at times of doubt and uncertainty. If it was not for Martin Banwell I

never would have made it to the point where I am now. Thank you very much for your guidance and

for your patience with me.

Thank you to Dr Brett Schwartz for being both my lab mate and also for his role as a member of my

supervisory panel. On countless occasions he has given me pivotal ideas which would push forward

my research into completely new directions. I never would have finished my work on the

epi-kirkamide if it hadn’t been for Dr Schwartz sharing his expertise and profound knowledge with me

and providing me with the relevant ideas to bring my research to a successful conclusion. I would

also like to thank Associate Professor Malcolm McLeod for his role as a member of my supervisory

panel. His feedback and his ideas which he shared with me on numerous occasions during our

discussions have sharpened my perspective on how and where to direct my research. I thank the

technical staff in the Research School of Chemistry for all their support. Thank you to Anitha

Jeyasingham, Joe Boileau, Adam Carroll and Thy Truong for all the mass specs you ran for me. Also, a

big thank you to Daniel Bartkus for all your work you invested into setting up the bioreactor and

helping me with the actual biotransformation. Thank you also to Drs Paul Carr and Jas Ward for all

the X-ray structures you ran for me. Thank you also to Drs Hideki Onagi and Nicholas Kanizaj for not

only being helpful in the lab, but also for being two very good friends.

Also I would like to thank the various project and visiting students I had the pleasure of supervising

and working with. Thank you to Alfred Fung, Michael Clark and Yun Qiu for your hard work.

A great thank you to my beautiful housemates Jenny and Nick for always making me feel at home,

and also to Daniel Smith for your dark humour and sarcasm, that helped me through so many

difficult situations. Thanks also to Moira, Zoë and Brad for tolerating my existence. I would also like

to thank my very good friend Junna Hayashi for all the beautiful and vibrant times we had together.

Without you my time here at the RSC and in Australia would have been far less enjoyable. I will

always cherish the memories of the expeditions we went on, but also the dinner and movie nights

we had. Thank you also all the members of the HDR Student Representative Committee. It was a

pleasure working with you towards an even better RSC.

Table of Contents

Declaration

i

Acknowledgements

ii

Table of Contents

iv

Publications

v

Relative Contributions to Publications

vii

Abstract

1

Synopsis

2

Thesis Overview

3

Statement of Contribution

20

Publication One

24

Publication Two

36

Publication Three

157

Publication Four

238

Publication Five

264

Publications

The following list details the publications that have resulted from the author’s research work

performed during his candidature for the Degree of Doctor of Philosophy

Publications:

1.

The Palladium-catalysed Ullmann Cross

-

coupling Reaction:

A Modern Variant on a Time-honored Process

Faiyaz Khan, Michael Dlugosch, Xin Liu and Martin G. Banwell

Accounts of Chemical Research, 2018, 51, 1784-1795.

2.

Palladium-Catalyzed Ullmann Cross-Coupling of β-Iodoenones and β-Iodoacrylates with

o-Halonitroarenes or o-Iodobenzonitriles and Reductive Cyclization of the Resulting Products

To Give Diverse Heterocyclic Systems

Faiyaz Khan, Michael Dlugosch, Xin Liu, Marium Khan, Martin G. Banwell, Jas S. Ward, and

Paul D. Carr, Organic Letters 2018, 20, 2770–2773.

3.

Reductive Cyclization of o-Nitroarylated-α,β-Unsaturated Aldehydes and Ketones with

TiCl

/HCl or Fe/HCl Leading to 1,2,3,9-Tetrahydro-4H-carbazol-4-ones and Related

Heterocycles

Yun Qiu, Michael Dlugosch, Xin Liu, Faiyaz Khan, Jas S Ward, Ping Lan, and Martin G Banwell

J. Org. Chem., 2018, 83, 12023–12033.

4.

Synthesis of a Highly Functionalised and Homochiral 2-Iodocyclohexenone Related to the

C-Ring of the Polycyclic, Indole Alkaloids Aspidophytine and Haplophytine

Michael Dlugosch and Martin Banwell

Australian Journal of Chemistry, 2018, 71, 573-579.

Article featured on the cover of the journal

5.

Syntheses of Structurally and Stereochemically Varied Forms of C

N Aminocyclitol

Derivatives from Enzymatically-derived and Homochiral cis-1,2-Dihydrocatechols

6.

Chemical Syntheses of the Cochliomycins and Certain Related Resorcylic

Acid Lactones

Commentary on the Contributions of Mr Michael Dlugosch to the

Six Papers Included in this PhD Thesis by Publication

Publication 1. This is a review article that was written by Professor Martin Banwell. It incorporates

descriptions of research on palladium-catalyzed Ullmann cross-coupling reactions conducted by the

co-authors including the author of this thesis.

Publication 2. Professor Martin Banwell proposed the research work reported in this article. The

author carried out 40 % of the reported laboratory work. In addition he collated and formatted 40 %

of the reported spectral data presented in the Supporting Information. The author also wrote 40 %

of the Experimental Section and conducted relevant literature surveys. Professor Martin Banwell

wrote the body of the paper.

Publication 3. The initial idea for this project came from Professor Martin Banwell. The author

carried out 65 % of the laboratory work reported in this article. In addition, he collated and

formatted 60 % of the reported spectral data presented in the Supporting Information. The author

also wrote 65 % of the Experimental Section and conducted relevant literature surveys. Professor

Martin Banwell wrote the body of the paper.

Publication 4. The initial idea for this project came from Dr Lorenzo White. The author carried out

the entirety of the laboratory work reported in this article. In addition, he collated and formatted

the entirety of the reported spectral data presented in the Supporting Information. The author also

wrote the entirety of the Experimental Section and conducted relevant literature surveys. Professor

Martin Banwell wrote the body of the paper.

Publication 5. The initial idea for this project came from Professor Martin Banwell. The author

carried out the entirety of the laboratory work associated with the reported synthesis of

epi-kirkamide (Schemes 1 and 2) and the enantiomeric switching regime (Scheme 6). In addition, he

collated and formatted the entirety of the reported spectral data sets presented in the Supporting

Information. He also wrote the entirety of the corresponding portion of the Experimental Section

and conducted relevant literature surveys on epi-kirkamide. He also conducted extensive research of

the relevant literature pertaining to the synthesis of various kirkamide analogues. Professor Martin

Banwell wrote the body of the paper.

Publication 6. This is a review article that was written by Professor Martin Banwell. It incorporates

Abstract

Publication 1 comprises a review article concerned with palladium-catalyzed Ullmann cross-

coupling reactions. Specifically, it details modern variants of these type of reactions and their

extensive use, most notably by the Banwell group, in the synthesis of various heterocyclic systems,

including ones encountered in natural products. Publication 1 contextualizes the research described

in Publications 2-4.

Publication 2 is concerned with the palladium-catalyzed Ullmann cross-coupling reactions of

β-iodoenones or β-iodoacrylates with o-iodonitrobenzenes or o-iodobenzonitriles, as well as the

reductive cyclization of the resulting products to give various heterocyclic systems. Thus, this

publication is concerned with a two-step approach to the synthesis of structurally diverse and

biologically active heterocycles, including quinolones and benzomorphans which are normally only

accessible via multistep-syntheses.

Publication 3 outlines research on palladium-catalyzed Ullmann cross-coupling reactions of

α-iodoenones with o-iodonitrobenzenes and the reductive cyclization of the ensuing coupling products.

Specifically, it details the exploration of two distinct modes of reductive cyclization that allow for the

synthesis of structurally “complementary” heterocyclic ring systems from a common precursor.

Publication 4 describes a chemoenzymatic synthesis of a highly functionalized and homochiral



-iodocyclohexenone that it is expected will serve as a precursor, through the application of

palladium-catalyzed Ullmann cross-coupling and reductive cyclization reactions, to the complex

indole alkaloids aspidophytine and haplophytine. The synthesis starts with an enantiomerically pure

cis-1,2-dihydrocatechol that is itself obtained through the whole-cell biotransformation of

bromobenzene.

Publication 5 is concerned with the developing syntheses of certain C

N aminocyclitols, a significant

group of biologically active natural products. In particular, this paper details chemoenzymatic total

syntheses of several novel compounds within the class, including analogues of the recently isolated

natural product kirkamide. The syntheses exploit, as starting materials, enzymatically-derived and

homochiral cis-1,2-dihydrocatechols obtained from either iodo- or bromo-benzene. Methods for

obtaining the enantiomers of the reported C

N aminocyclitol derivatives have been identified. Once

again, palladium-catalyzed cross-coupling chemistries were employed as key steps in these

syntheses.

Publication 6 is concerned with developing chemical syntheses of cochliomycins and related,

synthesis of an important subset of the large class of structurally distinct and biologically significant

natural products known as resorcylic acid lactones.

Synopsis

Cross-coupling reactions provide a particularly effective means for the formation of carbon-carbon

bonds. Many, well-established methods for forming such bonds now exist, perhaps the most

noteworthy being palladium-catalyzed cross-couplings that involve the linking of a halide or

pseudo-halide with an organometallic or metalloid species. While these reactions often give good yields of a

single product, one drawback is the need to form the requisite organometallic species, usually from

the corresponding organo-halide. While the classical Ullmann cross-coupling reaction has the

advantage that it can affect the direct coupling of two distinct organo-halides, harsh reaction

conditions are usually involved (temperatures in excess of 250 °C are frequently required) and often

homo-coupling is the predominant, if not the only process observed.

_{The palladium-catalyzed}

Ullmann cross-coupling affords many of the advantages of the standard palladium-catalyzed

processes as well as those associated with the original Ullmann reaction. As such, it is now possible

to carry out hetero-couplings of two distinct organo-halides under mild conditions.

The focus of the research described in this thesis is the deployment of palladium-catalyzed Ullmann

cross-coupling reactions in the synthesis of biologically active heterocyclic systems, as well as the

total synthesis of natural products. A common theme is the cross-coupling of iodoenones with

substituted o-iodo- or o-bromo-benzenes as shown, for example, in Scheme 1. The substituents (R’)

associated with the haloarenes are usually strongly electron-withdrawing ones, such as nitrile or

nitro groups. The proposed reaction mechanism for this type of couplings is based on a previously

reported reaction mechanism by Shimizu and co-workers.

_{In the first step the Pd(0) catalyst}

Scheme 1: An Example of the Palladium-Catalyzed Ullmann Cross-Coupling Reaction and the

Proposed Reaction Mechanism

Such palladium-catalyzed Ullmann cross-couplings can be conducted using a range of iodinated

enones, as described in Publications 2 and 3, and so providing ready access to diverse heterocyclic

systems in just one or two steps. As described in Publication 4, it is anticipated that the reaction can

also be deployed for the assembly of more elaborate systems. The application of related

cross-coupling reactions to syntheses of natural products and natural product analogues are described in

Publications 5 and 6.

Thesis Overview

Publication 1: The Palladium-catalysed Ullmann Cross-coupling Reaction:

A Modern Variant on a Time-honored Process

reaction sequence shown in Scheme 2 is also one direct example of the author’s immediate

contributions to this publication.

Scheme 2: Synthesis of Indole 4

Another example is the synthesis of a class of compounds called carbolines. There are four isomeric

carbolines, as shown in Figure 1, and each of these is encountered in natural products and/or within

pharmacologically significant compounds.

Figure 1: The Structures of the Four Isomeric Carbolines

The synthesis of the carboline-type natural product harman (13)

_{(possessing anti-HIV activity}

₎

shown in Scheme 3 further exemplifies the utility of the protocols developed by the Banwell group.

Scheme 3: Synthesis of the Natural Product Harman

Publication 2. Palladium-Catalyzed Ullmann Cross-Coupling of β-Iodoenones and β-Iodoacrylates

with o-Halonitroarenes or o-Iodobenzonitriles and Reductive Cyclization of the Resulting Products

to Give Diverse Heterocyclic Systems

Previous work conducted by the Banwell group on the palladium-catalyzed Ullmann cross-coupling

reaction was largely focussed on the coupling of α-iodoenones with o-halonitrobenzenes.

Transformations of this type provide access to different types of natural products including the

carbazoles shown in Figure 2.

Figure 2: Structures of Diverse Carbazoles

The successful syntheses of the members of the the uleine alkaloid family shown in Figure 3 further

highlight the power of such methodologies.

Figure 3: Members of the Uleine Alkaloid Family Accessible Using the Palladium-Catalyzed Ullmann

The research reported in Publication 2 is complementary to such earlier work. The focus in this

publication is on the participation of β-iodoenones and β-iodoacrylates (rather than, say,

α-iodoenones) in palladium-catalyzed Ullmann cross-coupling reactions. Depending on the precise

nature of such coupling partners, as well as the methods used for the reductive cyclization, then

various heterocyclic systems including quinolones, dihydroquinolones, benzomorphanes and

naphthydrines can be obtained. A number of these have now become much more readily accessible

as a result. The benzomorphans reported in this publication are of particular interest, as many of

them have a number of notable medicinal properties including by serving as analgesics.

_{Scheme 4}

highlights some such transformations.

Scheme 4: Palladium-Catalyzed Ullmann Cross-Coupling of β-iodoenones with o-Halonitrobenzenes

Giving Access to Heterocyclic Systems such as Azacoumarins and Benzomorphans

In this study it was also shown that depending upon the mode of reduction of the initial Ullmann

cross-coupling product different cyclization products can be obtained. For instance, if compound 37

(Scheme 5) is treated with Fe in AcOH/HCl then quinolone 38 is obtained while exposing the same

substrate to standard hydrogenation conditions (H

/Pd on C) affords the fully reduced product,

namely dihydroquinolone 36.

On the basis of the studies reported in Publication 2, it is clear that palladium-catalyzed Ullmann

cross-couplings involving β-iodoenones and β-iodoacrylates provide a versatile means for obtaining

hitherto unknown or less readily accessible heterocyclic frameworks.

Publication 3: Reductive Cyclization of o-Nitroarylated-α,β-Unsaturated Aldehydes and Ketones

with TiCl

/HCl or Fe/HCl Leading to 1,2,3,9-Tetrahydro-4H-carbazol-4-ones and Related

Heterocycles

Publication 3 further articulates the utility of the palladium-catalyzed Ullmann cross-coupling

/reductive cyclization sequence. In particular, it focuses on different methods for effecting the

reductive cyclizations of the coupling products. Significantly, depending upon the mode of the

reductive cyclization a given coupling product may afford distinct heterocyclic products. This further

extends the range of heterocycles that can be obtained. In particular, Publication 3 focuses on the

complementary behaviours of the H

/Pd on C and the TiCl

/HCl reduction systems. So, as shown in

Scheme 6, if coupling product 40 is treated with H

in presence of Pd on C then it reacts to give

product 39 while on treatment with TiCl

/HCl then congener 41 is obtained.

Scheme 6: Divergent Reductive Cyclization Pathways for Compound 40

Similarly, as shown in Scheme 7, while subjection of cross-coupling products 46 or 47 to reductive

cyclization using H

and Pd on C provides indole 45, on treating the same substrates with TiCl

in HCl

Scheme 7: Synthesis of Reductive Cyclization Products 45 and 48

In contrast, the readily available cinnamaldehyde derivative 49 shown in Scheme 8 affords the

known anti-proliferative agent 50

_{on treatment with TiCl}

3

/HCl in acetone.

Scheme 8: TiCl

-Mediated Cyclization of Compound 49

In a further example of the utility of such cyclization reactions, levoglucosenone derivative 51

provides, as depicted in Scheme 9, the tetracyclic product 52 upon treatment with TiCl

in HCl.

Scheme 9: TiCl

-Mediated Cyclization of Compound 51 to Give the Tetracyclic

Levoglucosenone-Based Compound 52

With this method it is also possible to form novel dihydroquinolines. Thus, ketones such as acetone

can be incorporated into the reductive cyclization product. As illustrated in Scheme 10, this

presumably occurs via Schiff base condensation, electrocyclic ring-closure then a prototropic shift

and accompanying re-aromatization. If, for instance, compound 31 is reacted with TiCl

/HCl in

53. The amine residue so-formed then undergoes a Schiff base condensation with the added ketone

to yield intermediate 55 that undergoes electrocyclic ring closure to give intermediate 56. A

prototropic shift and accompanying re-aromatization then leads to the final product 54, the

structure of which was confirmed by single-crystal X-ray analysis.

Scheme 10: Formation of Dihydroquinoline 54 from Cross-coupling Product 31 and Acetone in the

Presence of TiCl

/HCl

As shown in Scheme 11 a range of other dihydroquinolines was prepared by simply reacting

compound 53 with aldehydes or ketones, usually in presence of aqueous HCl. For instance, when

this substrate was reacted with benzaldehyde, then product 57 was obtained. Similarly, the reaction

between compound 53 and butanone afforded compound 58, while the reaction involving

cyclohexanone gave the spirocyclic product 59.

Scheme 11: Acid-Promoted Reactions of Compound 53 with Aldehydes or Ketones to Give

Overall, then, Publication 3 builds, in a distinctly complementary way, on the work reported in

Publication 2.

Publication 4: Synthesis of a Highly Functionalised and Homochiral 2-Iodocyclohexenone Related

to the C-ring of the Polycyclic, Indole Alkaloids Aspidophytine and Haplophytine

Aspidophytine is a constituent of the heterodimeric compound (+)-haplophytine (Figure 4) that

occurs in the Mexican cockroach plant Haplophyton cimididum.

_{Dried leaves of this plant have been}

used for their insecticidal properties since at least the Aztec era. A range of synthetic studies has

been conducted on the total synthesis of aspidophytine, the first synthesis of the

(–)-enantiomeric form having been reported by Corey and his co-workers in 1999.

_{This was}

followed by the reports of Fukuyama (2003)

_{, Padwa (2006)}

_{, Marino (2006)}

_{, Nicolaou}

(2008)

_{, Tokuyama (2013)}

_{and Qiu (2013).}

Figure 4: Structures of the Alkaloids Haplophytine and Aspidophytine

A nine step synthesis of a highly functionalized and homochiral 2-iodocyclohexenone that is related

to the C-Ring of aspidophytine and haplophytine is reported in Publication 4. Unlike all previously

reported asymmetric total syntheses of these compounds, a chemo-enzymatic approach is used to

establish the required functionality and stereochemistry.

Scheme 12: Synthesis of the Homochiral 2-Iodocyclohexenone 70

The aminoalkyl chain associated with the target 2-iodocyclohexenone was introduced via Suzuki–

Miyaura cross-coupling of compounds 63 and 64. The quaternary stereocenter of the target was

then established using the allylic alcohol moiety embedded within compound 66 by treating it with

dimethylformamide dimethyl acetal (DMADMA) and thus effecting an Eschenmoser–Claisen

rearrangement. Deprotection of the newly generated allylic alcohol, followed by oxidation and

Johnson



-iodination then gave α-iodoenone 70.

Scheme 13: Possible Elaboration of the Palladium-Catalyzed Ullmann Cross-Coupling Product 70 to

Tetracyclic Compound 73

Scheme 14 illustrates a series of possible further reactions, including a Corey–Winter olefination,

that could be applied to compound 73 and so yielding ent-aspidophytine. Compound 73 may be

reacted with 2-bromoethanol to yield amino-alcohol 74, which can then be mesylated. Treating the

indole moiety with a strong base should then lead to deprotonation and subsequently to an

intramolecular displacement of the mesylate and ring-formation. The unprotected diol in compound

76 would then be converted to the corresponding olefin via Corey–Winter olefination. Hydrolysis of

the dimethyl amide and esterification should then give ent-aspidophytine.

Publication 5: Syntheses of Structurally and Stereochemically Varied Forms of C

N Aminocyclitol

Derivatives from Enzymatically-derived and Homochiral cis-1,2-Dihydrocatechols

In 2015 the isolation of the new C

N aminocyclitol kirkamide as well as an eleven step synthesis of it

from methyl N-acetyl-D-glucosamine was reported by Gademann and co-workers (Scheme 15).

Scheme 15: Gademann’s Synthesis of Kirkamide

Kirkamide is found in leaf nodules of the plant Psychotria kirkii and likely produced by Candidatus

Burkholderia kirkii, a leaf symbiont of this plant.

_{Since kirkamide has shown to be toxic to aquatic}

arthropods and insects it might be acting as an anti-feedant and thus protecting the leaves of the

host plant.

In Publication 5 total syntheses of several derivatives of kirkamide, including an epimer, are

reported. In contrast to the previously reported synthesis, the approach taken in the author’s work is

a chemo-enzymatic one. The starting material for this purpose is the cis-dihydrocatechol 62, which

also served as the starting material for the synthesis described in Publication 4.

In Scheme 16 the total synthesis of epi-kirkamide is shown. Thus, treatment of previously reported

acetamide derivative, 87, with KHMDS gave, via the intermediate aziridine 88, the isomeric oxazoline

89. The introduction of the hydroxymethyl group associated with the C

N aminocyclitols was

iodoalkene 91 in presence of N,O-dimethylhydroxylamine under a carbon monoxide atmosphere

gave the α,β-unsaturated Weinreb amide 92. A two-step reduction of this amide (using lithium

aluminium hydride for the formation of the corresponding aldehyde and subsequent Luche

reduction) yielded compound 95 and global deprotection of this using aqueous acetic acid then gave

epi-kirkamide (96).

Scheme 16: A Total Synthesis of epi-Kirkamide (96)

Scheme 17: Synthesis of Alkenyl Iodide 102 from cis-Dihydrocatechol 62

Compound 102 was also synthesized in a more direct manner from the cis-dihydrocatechol 103

(Figure 5). However, while compound ent-62 is known, congener ent-103 is not. As such, only

synthetic sequences starting from the bromo-compound 62 can be used to produce the

enantiomeric forms of the targeted kirkamide analogues.

Figure 5: cis-Dihydrocatechol 103

Compound 102 was engaged in two carbopalladation reactions (Scheme 18) and thereby affording

the C

N-aminocyclitols 104 and 105. Furthermore, upon treating compound 105 with freshly

Scheme 18: Synthesis of New C

N-Aminocyclitol Derivatives 104, 105 and 106 from Iodoalkenyl 102

The three new aminocyclitols 104, 105 and 106 thus obtained have the potential to serve as

precursors to a diverse range of aminocarbasugars. Compounds 104 and 105 can also be regarded as

precursors to ent-kirkamide (ent-86) (Figure 6).

Figure 6: ent-Kirkamide (ent-86)

Publication 6. Chemical syntheses of the cochliomycins and certain related resorcylic acid lactones

Small molecule natural products (SMNPs) are often utilized as therapeutic agents, as precursors to

these or as an inspiration for them.

_{Among SMNPs the resorcylic acid lactones (RALs) are notable}

for the diversity of their biological activities, their unique structural features and their frequent

occurrence among fungal metabolites.

_{This article reviews synthetic studies on and the biological}

and is particularly interesting from a medicinal point of view because it shows good binding affinity

for human opioid receptors.

Figure 7: Structures of Various Cochliomycins

Scheme 19 shows the total synthesis of cochliomycin C as reported by the Banwell group. This

synthesis featuring a Stille cross-coupling as a crucial step is another example highlighting the broad

applicability of cross-coupling reactions for the total synthesis of natural products.

References

1

_{Ullmann F., Bielecki J. , Chem. Ber., 1901, 34, 2174–2185}

2

_{Shimizu N., Kitamura T., Watanabe K., Yamaguchi T, Shigyo H., Ohta T., Tetrahedron Lett., 1993, 34,}

3421-3424

3

_{Yan, Q.; Gin, E.; Banwell, M. G.; Willis, A. C.; Carr, P. D., J. Org. Chem., 2017, 82, 4328-4335}

4

_{Ishida J., Wang H.K., Oyama M., Cosentino M.L., Hu C.Q., Lee K.H., J. Nat. Prod., 2001, 64, 958-960}

5

_{Yan Q., Gin E., Wasinska-Kalwa M., Banwell M. G., J. Org. Chem. 2017, 82, 4148−4159}

6

_{Tang F., Banwell M. G., Willis A., J. Org. Chem. 2016, 81, 2950-2957}

7

_{Cittern, P.A., Kapoor V.K., Parfitt R.T., J. Med. Chem., 1986, 29, 1929–1933}

8

_{Miao B., Zheng Y., Wu P., Li S., Ma S. Adv. Synth. Catal. 2017, 359, 1691}

9

_{Snyder H.R., Fischer R.F., Walker J.F., Els H.E., Nussberger G.A., J. Am. Chem. Soc. 1954, 76, 4601-4605}

10

_{He F., Bo Y., Altom J.D., Corey E.J., J. Am. Chem. Soc. 1999, 121, 6771-6772}

11

_{Sumi S., Matsumoto K., Tokuyama H., Fukuyama T., Org. Lett., 2003, 5, 1891-1893}

12

_{Sumi S., Matsumoto K., Tokuyama H., Fukuyama T., Tetrahedron Lett., 2003, 59, 8571-8587}

13

_{Mejía-Oneto J.M., Padwa A., Org. Lett., 2006, 8, 3275-3278}

14

_{Mejía-Oneto J.M., Padwa A., Helv. Chim. Acta, 2008, 91, 285-302}

15

_{Marino J.P., Cao G., Tetrahedron Lett., 2006, 47, 7711-7713}

16

_{Nicolaou K.C., Dalby S.M., Majumder U., J. Am. Chem. Soc., 2008, 130, 14942-14943}

17

_{Satoh H., Ueda H., Tokuyama H., Tetrahedron, 2013, 69, 89-95}

18

_{Yang R., Qiu F.G., Angew. Chem. Int. Ed., 2013, 52, 6015-6018}

19

_{Sieber S., Cerlier A., Neuburger M., Grabenweger G., Eberl L., Gademann K., Angew. Chem. Int. Ed. 2015,}

54, 7968-7970

20

_{VanOevelen S., DeWachter R., Vandamme P., Robbrecht E., Prinsen E., Int. J. Syst. Evol. Microbiol. 2002,}

52, 2023 –2027

21

_{Carlier A.L., Eberl L., Environ. Microbiol. 2012, 14, 2757- 2769; Carlier A.L., Omasits U., Ahrens C.H.,}

Eberl L., Mol. Plant-Microbe Interact. 2013, 26, 1325 –1333

22

_{Dias, D.A. Urban, S. Roessner, U. Metabolites 2012, 2, 303-336}

23

_{Winssinger N. Barluenga S. Chemical Communications 2007, 22-36}

24

_{Zhang Y. Dlugosch M. Jübermann M. Banwell M.G. Ward J.S. J. Org. Chem., 2015, 80, 4828-4833}

25

_{Gao J., Radwan M.M., Leon F., Dale O.R., Husni A.S., Wu Y., Lupien S., Wang X., Manly S.P., Hill R.A,}

The Palladium-Catalyzed Ullmann Cross-Coupling Reaction:

A Modern Variant on a Time-Honored Process

Faiyaz Khan, Michael Dlugosch, Xin Liu, and Martin G. Banwell

*

Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia

CONSPECTUS:

Cross-coupling reactions, especially those that are catalyzed by palladium, have revolutionized the way in

which carbon

−

carbon bonds can be formed. The most commonly deployed variants of such processes are the Suzuki

−

Miyaura,

Mizoroki

−

Heck, Stille, and Negishi cross-coupling reactions, and these normally involve the linking of an organohalide or

pseudohalide (such as a tri

fl

ate or nona

fl

ate) with an organo-metallic or -metalloid such as an organo-boron, -magnesium, -tin,

or -zinc species. Since the latter type of coupling partner is often prepared from the corresponding halide, methods that allow for

the direct cross-coupling of two distinct halogen-containing compounds would provide valuable and more atom-economical

capacities for the formation of carbon

−

carbon bonds. While the venerable Ullmann reaction can in principle achieve this, it has

a number of drawbacks, the most signi

fi

cant of which is that homocoupling of the reaction partners is a competitive, if not the

dominant, process. Furthermore, such reactions normally occur only under forcing conditions (viz., often at temperatures in

excess of 250

°

C). As such, the Ullmann reaction has seen only limited application in this regard, especially as a mid- to

late-stage feature of complex natural product synthesis. This Account details the development of the palladium-catalyzed Ullmann

cross-coupling reaction as a useful method for the assembly of a range of heterocyclic systems relevant to medicinal and/or

natural products chemistry. These couplings normally proceed under relatively mild conditions (<100

°

C) over short periods of

time and, usually, to the exclusion of (unwanted) homocoupling events. The keys to success are the appropriate choice of

coupling partners, the form of the copper metal employed, and the choice of reaction solvent.

At the present time, the cross-coupling partners capable of engaging in the title reaction are con

fi

ned to halogenated and

otherwise electron-de

fi

cient arenes and, as complementary reactants,

α

- or

β

-halogenated,

α

,

β

-unsaturated aldehydes, ketones,

esters, lactones, lactams, and cycloimides. Nitro-substituted (and halogenated) arenes, in particular, serve as e

ff

ective

participants in these reactions, and the products of their coupling with the above-mentioned carbonyl-containing systems can be

manipulated in a number of di

ff

erent ways. Depending on the positional relationship between the nitro and carbonyl groups in

the cross-coupling product, the reduction of the former group, which can be achieved under a range of di

ff

erent conditions,

provides, through intramolecular nucleophilic addition reactions, including Schi

ff

base condensations, access to a diverse range

of heterocyclic systems. These include indoles, quinolines, quinolones, isoquinolines, carbazoles, and carbolines. Tandem

variants of such cyclization processes, in which Raney cobalt is used as a catalyst for the chemoselective reduction (by

dihydrogen) of nitro and nitrile groups (but not ole

fi

ns), allow for the assembly of a range of structurally challenging natural

products, including marinoquinoline A, (

±

)-1-acetylaspidoalbidine, and (

±

)-gilbertine.

1. INTRODUCTION

Arguably, carbon

−

carbon bond formation is the most

important process in organic chemistry, and the development

of means for doing so has been a source of conscious e

ff

ort for

almost two centuries.

In modern times, cross-coupling

reactions, perhaps most especially those catalyzed by

palladium, nickel, copper, and iron species, have revolutionized

the way in which more complex organic compounds are

assembled from simpler ones.

Named reactions such as the

Suzuki

−

Miyaura, Mizoroki

−

Heck, Stille, Sonogashira, and

Negishi cross-couplings immediately spring to mind in

considering such matters.

The coupling partners involved

in these processes are normally an organohalide or

metallic species that is, more often than not, obtained from a

halide precursor. In view of this and the frequently unstable/

sensitive nature of the organometallic species, there have been

many e

ff

orts directed at e

ff

ecting the reductive cross-coupling

of two structurally distinct organohalides, the most

con-spicuous examples of which involve adaptations of the

venerable Wurtz

and Ullmann

reactions. In their traditional

forms, however, these processes have not found extensive

application because of competition from homocoupling

reactions and/or the need to use rather aggressive reaction

conditions that are incompatible with other functionalities

Received: April 13, 2018

Article

pubs.acs.org/accounts

Cite This:Acc. Chem. Res.2018, 51, 1784−1795

Downloaded via AUSTRALIAN NATL UNIV on September 18, 2018 at 05:05:02 (UTC).

present in the substrates. In recent times, so-called

cross-electrophile couplings (XECs), especially ones carried out in

reductive mode and often involving multimetallic catalysts,

have come to the fore, with notable contributions having been

reported in the past few years by various groups.

The

versatility of such processes is quickly becoming apparent.

Herein we detail the outcomes of our own ongoing work

concerned with the development of the palladium-catalyzed

Ullmann cross-coupling reaction of structurally distinct, sp

-hybridized, halogen-associated electrophiles with one

anoth-er.

These reactions enable the construction of products that

are useful in their own right and/or can participate in reductive

cyclization reactions and thus a

ff

ording various heterocyclic

motifs encountered in a range of interesting natural products.

2. THE CLASSICAL ULLMANN REACTION

The Ullmann reaction (

Scheme 1

) was

fi

rst reported in 1901

and in the intervening period has found extensive application

in chemical synthesis, most notably in the reductive coupling

of aryl halides (e.g.,

1

) to form the corresponding symmetrical

biaryls (e.g.,

2

).

Its limitations also became evident rather

quickly. These include the need to use high reaction

temperatures (>200

°

C), the attendant functional group

incompatibilities, an inability to cleanly generate

unsym-metrical biaryls from two structurally distinct aryl halide

precursors (because of competing homocoupling processes),

and the frequently erratic yields obtained. Manifold e

ff

orts to

redress such de

fi

ciencies have been undertaken over the years,

including through the application of on-surface processes,

the

introduction of metal-chelating species,

and the use of

varying forms of copper as well as other metal species.

These

have had useful impacts, as summarized in a range of recent

review articles.

3. DISCOVERY OF THE PALLADIUM-CATAYLZED

ULLMANN CROSS-COUPLING REACTION

Some years ago, in connection with work directed toward

establishing a total synthesis of the alkaloid rhazinal,

a potent

spindle toxin, we required access to an arylated pyrrole. We

initially attempted to prepare this key intermediate through

conventional Ullmann cross-coupling of commercially available

o

-bromonitrobenzene (

1

) with the known iodinated pyrrole

3

(see

Scheme 2

), but only traces of target

4

were obtained.

Upon undertaking an extensive literature survey, we came

across the work of Thompson

and Shimizu,

both of whom

reported that the synthesis of certain arylated pyridines

through the Ullmann cross-coupling of the relevant aryl halide

and halogenated pyridine is greatly facilitated by the addition

of a palladium catalyst. Upon applying such observations to

our system,

using DMF as solvent and three equivalents of

compound

1

, we were able to obtain, under ultrasonication

conditions, target

4

in 88% yield (based on recovered starting

material (brsm)), with the major byproduct being 2,2

′

-dinitrobiphenyl (

2

) (55%) (

Scheme 2

).

These observations triggered extensive studies of the title

process that continue in our group to this day. These studies

have provided, through the reductive cyclization of the initially

formed cross-coupling products, useful new means for the

construction of a wide range of heterocyclic compounds,

including ones embodying previously unreported frameworks.

Details of these processes are presented in the following

sections and categorized according to the heterocyclic

frameworks that are generated.

4. APPLICATION TO THE SYNTHESIS OF

HETEROCYCLES

4.1. Indoles

Our

fi

rst e

ff

orts to comprehensively develop the title reaction

involved the cross-coupling of readily available

α

-halo-enones

and -enals with

o

-halonitroarenes and the reductive cyclization

of the ensuing

α

-arylated-enones and -enals to give indoles,

including annulated variants.

The simple reaction sequences

shown in

Scheme 3

serve to highlight the possibilities for the

assembly of such heterocycles, and others have since exploited

these processes in the total synthesis of a range of natural

products.

Some of our own e

ff

orts in this regard are detailed

in the next section.

In the course of optimizing these sorts of cross-coupling

processes, we established that a range of di

ff

erent sources of

Pd[0] can be used, that DMSO appears to be the optimal

solvent, that electron-de

fi

cient, halogenated arenes are

required, and that a lower reaction temperature leads to a

better ratio of cross-coupling to homocoupling products.

Indeed, in favorable circumstances the cross-coupling reactions

can be conducted at near ambient temperatures and essentially

to the exclusion of the homocoupling process. Thus, a close to

1:1 ratio of coupling partners could often be employed, an

important consideration in exploiting these processes in

complex natural product synthesis, where such transformations

are exploited at a late stage. Mechanistically speaking, we

believe that these couplings proceed as suggested by Shimizu

Scheme 1. Original (1901) Ullmann Reaction Resulting in

the Reductive Coupling of

o

-Bromonitrobenzene (1) To

A

ff

ord

o

,

o

′

-Dinitrobiphenyl (2)

Scheme 2. Palladium-Catalyzed Ullmann 1 and 3 Leading to Arylated Pyrrole 4

(see the penultimate section for details), wherein palladium[0]

oxidatively adds to the

α

-iodo-enone or -enal and the resulting

palladium[II] complex reacts with the ortho-cuprated

nitro-arene arising from the other coupling partner, thereby

producing a palladated intermediate that undergoes reductive

elimination to deliver the observed product (and, of course,

regenerates the Pd[0] catalyst). The nature of the copper used

in these reactions has some impact on the e

ffi

ciency of the

process, with freshly prepared activated copper

being

particularly e

ff

ective though somewhat tedious to prepare.

The simple expedient of adding some sand to the reaction

mixture containing normal copper powder (copper bronze),

and thus continuously generating a fresh metal surface through

abrasion, is an operationally simple means of achieving often

the desired process,

although the precise origins of this

bene

fi

t remain to be fully understood.

Highly functionalized indolic substructures are encountered

in therapeutically signi

fi

cant alkaloids such as vincristine

(

Scheme 4

), and we sought to establish methods for

assembling these using our protocols.

In a representative

process,

α

′

-carbomethoxylated cycloheptenone

12

was

sub-jected to Pinhey arylation with plumbated indole

13

, thereby

a

ff

ording compound

14

, which was itself engaged in a

Johnson-type

α

-iodination

reaction to a

ff

ord iodide

15

. The

palladium-catalyzed Ullmann cross-coupling of this last

compound with

o

-iodonitrobenzene (

5

) gave product

16

,

which upon reductive cyclization a

ff

orded bis(indole)

17

Scheme 3. Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Sequences Leading to Indoles 8 and 11

Scheme 4. Synthetic Sequence Leading to Bis(indole) 17 Resembling the Southern Hemisphere of Vincristine

Scheme 5. Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Sequence Leading to Oxindole 20

4.2. Oxindoles

Oxindoles, which represent privileged structures in medicinal

chemistry and motifs encountered in biologically active natural

products,

are readily obtained using analogous processes

wherein an

α

-brominated

α

,

β

-unsaturated cycloimide, lactam,

or lactone is used as the coupling partner in a reaction with an

o

-halonitroarene and the product of this process then subjected

to reductive cyclization.

The e

ffi

cient

5

and

18

(

Scheme 5

)

to produce arylated

N

-methylmaleimide

19

followed by its

reductive cyclization under standard conditions to give

oxindole

20

is illustrative of these types of processes.

4.3. Quinolines and Related Heterocycles

A further extension of our original processes, as shown in

Scheme 3

, has allowed the formation of quinolones and related

coupling of arene

2

with aldehyde

21

a

ff

ords arylated enal

22

,

which, upon reductive cyclization, produces

cyclopenta-annulated quinolone

23

. In a related but less e

ffi

cient manner,

cross-coupling of compounds

2

and

24

a

ff

ords ester

25

which

upon reductive cyclization delivers the 2-quinolone

26

. By

similar means a range of alternately substituted/annulated

quinolones, phenanthridines, and 6(5

H

)-phenanthridinones

can be obtained. The capacity to generate electrophiles such as

21

directly from the corresponding ketone (in this case

cyclopentenone) through a Vilsmeier

−

Haack haloformylation

reaction is likely to enhance the utility of these processes.

4.4. Carbazoles

When

α

-iodocyclohex-2-en-1-ones are cross-coupled with

halogenated nitroarenes such as

1

and

5

using the protocols

Scheme 6. Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Sequences Leading to Quinoline 23 and

Quinolone 26

Scheme 7. Synthetic Routes to the Carbazole Natural Products Clauszoline K (32) and Karapinchamine A (34)

that their fully aromatic counterparts (viz., carbazoles) are

encountered in a wide range of biologically active natural

products, we sought to produce such heterocycles using

variations of our earlier protocols. The routes to clauszoline K

and karapinchamine A shown in

Scheme 7

are illustrative of

the possibilities the title reaction o

ff

ers in this regard.

Thus,

reductive cross-coupling of electrophiles

27

and

28

under our

now standard conditions a

ff

orded product

29

(80%), which

upon reductive cyclization using dihydrogen in the presence of

Raney nickel a

ff

orded tetrahydrocarbazole

30

(65%). This

could then be oxidized to its fully aromatic counterpart,

namely carbazole

31

(88%), upon exposure to 10% Pd on C in

diphenyl ether at 210

°

C (various attempts to e

ff

ect the

conversion

29

→

31

in a direct manner, or at least in a

one-pot-process, have been unsuccessful to date). Upon exposure

of compound

31

to

2,3-dichloro-5,6-dicyano-1,4-benzoqui-none (DDQ) it was oxidized, in 66% yield, to the natural

product clauszoline K (

32

). On the other hand, treatment of

compound

31

with BBr

e

ff

ected cleavage of the associated

ether residue and, thereby, the formation of the anticipated

phenolic product

33

(84%). Deprotonation of the latter

compound with

n

-butyllithium and reaction of the ensuing

anion with geranyl bromide resulted in alkylation at nitrogen

and the formation of the carbazole-containing natural product

karapinchamine A (

34

), which was obtained in 50% yield.

4.5. Carbolines

There are four isomeric carbolines, namely, the

α

,

β

,

γ

, and

δ

forms (

35

−

38

, respectively;

Figure 1

), and each of these

frameworks is encountered in both natural products and

pharmacologically active agents.

While various methods have

been developed for their synthesis, a uni

fi

ed approach to them

had remained elusive until our recent deployment of the title

cross-coupling reaction for this purpose.

An illustrative example of our approach is presented in

Scheme 8

. It starts with the palladium-catalyzed Ullmann

cross-coupling of bromonitropyridine

39

with readily available

α

-iodinated cyclohexenone

40

. Engaging the ensuing product

41

(80%) in a reductive cyclization reaction gives

tetrahy-drocarboline

42

(83%), which is then dehydrogenated to give

the fully aromatic compound

43

(83%) representing the

structure of the natural product harman.

The challenge associated with deploying this type of

approach to the carbolines is the need to construct the

requisite polysubstituted pyridine-based coupling partner.

Thus, for example, the nitration reaction associated with the

synthetic sequence leading to compound

39

also produced a

regioisomer, and these could only be separated from one

another by HPLC techniques.

4.6.β-Haloenones and Related Compounds as Cross-Coupling Partners

Recently we have established that

β

-haloenones such as

44

couple particularly e

ff

ectively with electrophiles including

5

(

Scheme 9

) to form the anticipated cross-coupling product

45

(91%), a compound that upon exposure to standard reductive

cyclization conditions using methanol as the solvent a

ff

ords

3,4-benzomorphan

46

in 73% yield.

In a further illustration

of the extensive utility of these types of processes, the coupling

of brominated pyridine

47

with the

β

-iodinated crontonate

48

proceeded with retention of con

fi

guration and a

ff

orded the

anticipated product

49

(84%). Reductive cyclization of this last

compound using iron

fi

lings in an acidic medium then gave the

1,8-naphthyridin-2(1

H

)-one

50

(76%). Interestingly,

o

-iodo-benzonitriles can be engaged in related couplings,

although

these are less e

ffi

cient than those involving iodinated

nitroarenes, presumably because of the weaker

electron-withdrawing properties of the cyano group.

4.7. Formation of Unsymmetrical Biaryls

An obvious application of the title reaction is in the production

of unsymmetrical biaryls. While we have yet to explore such

processes in any comprehensive fashion, early indications have

been very positive. Thus, as shown in

Scheme 10

for example,

the cross-coupling of aryl iodide

51

with bromide

52

under our

by now standard conditions provided the desired biaryl

53

(60%).

This last compound was readily elaborated to the

alkaloid zephycandidine III, a natural product reported to

possess acetylcholinesterase (AChE) inhibitory properties,

which were not evident in the synthetically derived material

despite the spectroscopic equivalence of the natural and

synthetic materials. More pertinent to the present discussion is

that all our attempts to prepare compound

53

and related

systems using Suzuki

−

Miyaura cross-coupling reactions were

unsuccessful.

5. APPLICATION TO THE TOTAL SYNTHESIS OF

NATURAL PRODUCTS

As our understanding of the palladium-catalyzed Ullmann

cross-coupling reaction has developed, we have been exploiting

it on an increasingly frequent basis in developing syntheses of

various natural products. Such is our con

fi

dence in the

Figure 1.The four isomeric carbolines.

Scheme 8. Synthetic Route to the Carboline Natural

Product Harman (43)

conjunction with reductive cyclization reactions that enable the

conversion of the cross-coupling products into various

heterocyclic frameworks. Speci

fi

c examples are given in the

following sections.

5.1. Synthesis of Marinoquinoline A

As part of an ongoing interest in the cross-coupling chemistries

of pyrroles,

we were attracted to the development of a

synthesis of marinoquinoline A, an alkaloid isolated from a

marine gliding bacterium that displays AChE inhibitory

and

antimalarial activities. The route that we ultimately established

in obtaining this compound is shown in

Scheme 11

. It starts

with the palladium-catalyzed Ullmann cross-coupling of

o

-bromonitrobenzene (

1

) with iodinated pyrrole

54

to a

ff

ord the

target

55

in 74% yield. Signi

fi

cantly, all of our attempts to

e

ff

ect the Suzuki

−

Miyaura cross-coupling of compound

54

with

o

-nitrophenylboronic acid failed.

In a related vein, when

o

-iodonitrobenzene (

5

) was used as a coupling partner in this

process, its homocoupling (to give 2,2

′

-dinitrobiphenyl)

became the dominant process. Such outcomes highlight the

capacity to facilitate cross-coupling processes by attenuating

the reactivity of one substrate through changing the associated

halogen.

The elaboration of coupling product

55

to the target alkaloid

was straightforward and involved the initial addition of

methyllithium to the associated aldehyde residue and oxidation

of the resulting alcohol,

56

, to the corresponding methyl

ketone

57

using the Dess

−

Martin periodinane (DMP).

Reductive cyclization of this last compound to the target

framework was e

ff

ected using magnesium in methanol, and this

was accompanied by cleavage of the tosyl group, thus a

ff

ording

marinoquinoline A (

58

) in 85% yield.

5.2. Total Syntheses of the Aspidosperma Alkaloids Aspidospermidine, Limaspermidine, and

1-Acetylaspidoalbidine and Approaches to Vindoline

In a more elaborate reaction sequence and as part of an

ongoing campaign to develop a synthesis of the binary indole

−

indoline alkaloid vincristine (see

Scheme 4

), we

fi

rst developed

a route to the alkaloid aspidospermidine.

This entailed, as

one of two key steps, the cross-coupling of

α

-iodinated

cyclohexenone

59

with arene

5

to a

ff

ord product

60

in 75%

yield (

Scheme 12

). Compound

60

was readily elaborated to

azide

61

that upon heating engaged in an intramolecular [3 +

2] cycloaddition reaction followed by nitrogen extrusion to

a

ff

ord aziridine

62

, thereby establishing the piperidine ring

Scheme 9. Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Sequences Leading to Heterocycles 46 and 50

Scheme 10. Palladium-Catalyzed Ullmann Cross-Coupling of Halogenated Arenes 51 and 52 Leading to Biaryl 53, a Precursor

the Alkaloid Zephycandidine III

Scheme 11. Total Synthesis of Marinoquinoline A

then deployed in elaborating compound

62

to

aspidospermi-dine.

A related but more convergent protocol was employed in

obtaining the alkaloid limaspermidine.

As shown in

Scheme

13

, compounds

5

and

63

were cross-coupled to give the

α

-arylated enone

64

(85%). When this was subjected to

reductive cyclization using dihydrogen in the presence of

Raney cobalt, the indole-annulated and cis ring-fused

octahydroquinoline

65

was obtained in 85% yield. This

conversion involves the selective reduction of the nitro and

cyano groups within substrate

64

while the enone moiety

remains intact. As a result, the associated ketone carbonyl

engages in an intramolecular Schi

ff

base condensation reaction

with the aniline or

N

-hydroxyaniline arising from reduction of

the nitro group while the 1

°

amine arising from the cyano

residue undergoes a hetero-Michael addition reaction, thus

forming both the indole and piperidine rings in a one-pot

operation. The use of properly prepared Raney cobalt

is

critical to the success of this transformation because of the

chemoselectivities it allows for. If the more active Raney nickel

is used as the catalyst, then reduction of the carbon

−

carbon

double bond of the enone residue also occurs, with the result

that piperidine ring formation does not take place.

Elaboration of compound

65

to (

±

)-limaspermidine was

achieved over four additional steps, including several closely

related to those employed in the conversion of compound

62

into (

±

)-apsidospermidine (

Scheme 12

). Two additional

steps, including an oxidative cyclization reaction employing

mercuric acetate, were required to convert (

±

)-limaspermidine

into (

±

)-1-acetylaspidoalbidine.

The extension of the protocols de

fi

ned above in an

enantioselective approach to the alkaloid vindoline

(represent-ing a crucial substructure of vincristine) is shown in

Scheme

14

.

Cross-coupling of iodinated nitroarene

66

with

homochiral

α

-iodinated cyclohexenone

67

(a compound

obtained from an enzymatically derived

cis

-1,2-dihydrocate-chol

) gave the anticipated product

68

in 92% yield.

Reduction of this last compound using dihydrogen in the

presence of Raney cobalt resulted in the formation of the

tandem reductive cyclization product

69

(85%) embodying a

cis ring-fused octahydroquinoline. Over a further four steps

this could be elaborated to the hexacyclic compound

70

embodying many of the features of vindoline, which we are

seeking to convert into that alkaloid.

5.3. Formal Total Synthesis of the Cage-like Alkaloid Kopsihainanine A

The tandem reductive cyclizations of the palladium-catalyzed

Ullmann cross-coupling products

64

and

68

are presumed to

proceed under kinetic control, thus a

ff

ording cis ring-fused

products. Given that trans ring-fused perhydroquinolines are

encountered in a range of natural products, we sought methods

to access such systems. Despite extensive investigations of the

cyclization reactions, including examination of a range of

modi

fi

cations to the conditions employed, the cis ring-fused

products were invariably formed on an exclusive basis.

Scheme 12. Total Synthesis of (

±

)-Aspidospermidine

Scheme 13. Total Syntheses of (

±

)-Limaspermidine and (

±

)-1-Acetylaspidoalbidine

Therefore, we sought ways to e

ff

ect epimerization at the

ring-junction carbon center bearing the piperidine nitrogen. This

turned out to be a straightforward process, as illustrated in our

formal total synthesis of the cage-like alkaloid kopsihainanine A

(

Scheme 15

).

The reductive cyclization product

65

could be

converted, over

fi

ve steps, into the angularly allylated congener

71

, which upon exposure to iodosobenzene in

dichloro-methane at ambient temperatures was oxidized to the

corresponding imine

72

. Upon reduction of compound

72

with sodium borohydride, the epimeric octahydroquinoline

73

was obtained. Since this last compound has previously been

converted into kopsihainanine A, the illustrated synthetic

sequence constitutes a formal total synthesis of the racemic

modi

fi

cation of this alkaloid.

5.4. Syntheses of the Uleine Alkaloids and Approaches to the Strychnos Alkaloids

members of the uleine family of alkaloids.

Cross-coupling of

compounds

5

and

74

under the usual conditions a

ff

orded the

anticipated product

75

(88%), and the reductive cyclization of

this with dihydrogen in the presence of Raney cobalt a

ff

orded

the tetracyclic product

76

(60%) as a result of the same type of

tandem processes as shown in

Schemes 13

and

14

. Selective

Boc protection of the piperidine nitrogen within compound

76

a

ff

orded carbamate

77

, and this could be elaborated over two

steps, including a pyridinium chlorochromate-mediated

oxidation reaction to introduce a carbonyl moiety at the

methylene adjacent to the indole ring, to hydroxyketone

78

.

Reaction of this last compound with methyllithium proceeded

smoothly, and the resulting tertiary alcohol engaged in a

cycloetheri

fi

cation reaction upon treatment with protic acid.

Cleavage of the Boc group also occurred under these

conditions, and the resulting 2

°

amine was subjected to

reductive N-methylation to a

ff

ord (

±

)-gilbertine.

Scheme 14. Synthesis of Compound 70, an Analogue of the Alkaloid Vindoline

Scheme 15. Conversion of cis Ring-Fused Octahydroquinoline 65 into Its trans-Con

fi

gured Congener 73, an Advanced

Precursor to the Alkaloid Kopsihainanine A

stereoselective manner,

while the ABCDE ring system of the

Strychnos

alkaloids proved accessible by similar means.

6. MECHANISTIC AND SYNTHETIC OVERVIEW

Our current thinking about the title process is dominated by

the original mechanistic proposals of Shimizu.

Thus, as shown

in

Scheme 17

, aryl iodide

79

is presumed to react with the

added copper through an oxidative addition/reductive

deiodination process to give arylcopper(I)

80

, representing

the aryl anion synthon

81

. This reacts with the aryl cation

synthon

82

, which is produced through oxidative addition of

Pd[0] to the carbonyl-containing coupling partner

83

, thus

a

ff

ording intermediate

84

. The coupling event presumably

Scheme 16. Total Synthesis of the Alkaloid (

±

)-Gilbertine

Figure 2.Structures of the simpler uleine alkaloids.

Scheme 17. Mechanistic and Synthetic Analysis of a Key Example of the Palladium-Catalyzed Ullmann Cross-Coupling

Reaction and Certain Currently Problematic Substrates